The inventions described below relate to site specific delivery of therapeutic agents, structures and catheter systems to achieve site specific delivery of therapeutic agents, and means for implanting and using these systems to enable delivery of therapeutic agents to the body.
The devices and methods described in this application provide for safer and better treatment of various forms of heart disease. The forms of heart disease which may be treated with these devices and methods include angina pectoris and related causes such as ischemia, arrhythmia, stenosis and restenosis. Other conditions such as chronic heart failure, heart transplant infection and rejection can be treated. Each of these conditions involves regions of tissue which are diseased, and these diseased regions of the heart may be treated with various therapeutic agents.
Ischemia and myocardial infarct are two important cardiac disease states. Symptoms are those included in the constellation of symptoms referred to as angina pectoris, and include constricting pain in the chest and radiating pain in the arms. Ischemic tissue is tissue which is starved of oxygen and nutrients, usually because the tissue is not receiving adequate blood supply. It is characterized by limited metabolic processes which causes poor functionality, and may lead to fibrillation and death. In turn this hinders the normal functioning of the heart cells or myocytes in an ischemic region. Ischemia is reversible, such that cells may return to normal function once they receive the proper nutrients. If an ischemic, or damaged, region of the heart does not receive enough nutrients to sustain the myocytes they are said to die, and the tissue is said to become infarcted. Infarcted tissue may also lead to fibrillation and death, and infarction is irreversible. The onset of ischemia and infarction are often referred to as a heart attack.
A number of methods have been developed to treat ischemic regions in the heart. Systemic delivery of anti-ischemic agents such as nitrates or vasodilators reduces vascular resistance, thereby reducing the amount of work the heart must perform, which in turn allows the heart function properly even with reduced blood flow. These drugs are taken orally or by injection, and affect the entire body as well as the ischemic tissue. Ischemic tissue caused by clogged arteries or vascular obstructions are treated by removal of the vascular obstruction. This can be done with the systemic delivery of pharmacological agents such as TPA, urokinase, or antithrombolytics which can break up the obstruction. It can also be done with catheter based techniques intended to open clogged arteries and remove the vascular obstructions. These catheter-based techniques include percutaneous transluminal coronary angioplasty (PTCA), atherectomy, and stent placement. These techniques can increase myocardial blood flow (perfusion), thereby providing the heart with sufficient oxygen and nutrients. More drastic but very reliable procedures such as coronary artery bypass surgery can also be performed.
Recently, some references have proposed injection of therapeutic agents into myocardium through the coronary arteries. Unger, et al., Method To Foster Myocardial Blood Vessel Growth And Improve Blood Flow To The Heart, U.S. Pat. No. 5,244,460 (Sep. 14, 1993) proposed injection of angiogenic growth factors into the coronary arteries through a catheter, with the intention that the growth factors be perfused along with the blood flow into the myocardium. This approach is problematic because (1) all the tissue served by the coronary artery is supplied with angiogenic agent, even though only the region of artery including the occlusion and downstream regions requires the angiogenic agent and (2) to ensure adequate supply to the ischemic area, substantially more angiogenic growth factor than is needed to treat the ischemic area must be delivered to the coronary artery. This may be substantially more tissue than is in need of local drug delivery therapy. The growth factors will act in the tissue which the coronary arteries successfully perfuse. The excess growth factors may cause unwanted angiogenesis in tissue elsewhere in the body. The cornea is described by Unger as such a location, but perhaps more critical is inappropriate delivery of these factors to the brain. Additionally, placement of delivery devices within the coronary arteries as Unger describes will tend to obstruct these arteries and may augment occlusive thrombosis formation. There is a significant need for a means and method of minimizing the amount of growth factors for introducing angiogenesis by delivering these agents only to the site where they are most needed.
Several other cardiac disease states are related to the diseases already discussed. After stent placement, and after opening vessels using balloon angioplasty (PTCA), the vessels often lose patency over time. This loss of patency due to re-stenosis may be reduced by appropriate pharmacological therapy in the region of the artery. These problems have not been resolved, and current proposals included irradiating the blood vessel in the region of the balloon angioplasty or stent. Cardiac arrhythmias are abnormal rhythmic contractions of the myocardial muscle, often introduced by electrical abnormalities, or irregularities in the heart tissue. Arrhythmias arise from arrhythmogenic tissue, sometimes including a focal point referred to as the focus of the arrhythmia. Arrhythmogenic tissue is sometimes caused by ischemia and infarct, and is sometimes causes by other conditions such as an inherent defect in the heart. Arrhythmogenic tissue may also be treated by injection of therapeutic agents, injected in the same manner as is used to treat ischemia and infarct.
Local drug delivery provides many advantages. Approaches for local delivery of agents at a depth within a tissue enables the delivery of drugs to sites where they are most needed, reduces the amount of drugs required, increases the therapeutic index of the particular dosing regime, and increases the control over the time course of agent delivery. These, in turn, improve the viability of the drugs, lower the amount (and cost) of agents, reduce systemic effects, reduce the chance of drugxe2x80x94drug interactions, lower the risk to patients, and allow the physician to more precisely control the effects induced. Such local delivery may mimic endogenous modes of release, and address the issues of agent toxicity and short half lives. March, U.S. Pat. No. 5,840,059 describes a means of delivering therapeutic agents into a channel within the heart, but suffers the serious limitation in that the material will likely not be retained in the channels. The viscous carrier suggested by March to help retain the material within the channels poses substantial risk as embolic material should it escape from the channels and be released into the endocardial chamber. Our own applications have provided devices, methods, and formulations of therapeutic agents for use in treating various cardiac diseases. These applications have disclosed percutaneous delivery of therapeutic agents to the heart through the arterial system and the left heart, with devices and methods to enhance the retention of therapeutic agents within the heart wall.
The devices and methods described below provide for delivery of therapeutic substances to a depth within the heart muscle via the venous side of the heart, with a primary focus on delivery through the coronary sinus and through the right ventricular apex and septum. The devices and methods may be combined with percutaneous access catheters in order to provide for right heart delivery of therapeutic agents. The devices and methods may be combined with permanently implantable devices with and without the electrical sensing and stimulation capabilities, and they provide either sustained delivery of therapeutic agents locally over time via a fluid pathway, or may deliver fluid agents upon demand as a result of an event sensed by a patient are described. Devices and techniques for delivering drug microformulations such as microspheres and liposomes, and drug delivery structures from an acute use catheter system are also described.